Diets high in sugar and saturated fat ("Western" diets) contribute to the increased incidence of metabolic syndrome and cardiovascular disease (CVD). The mechanisms underlying Western diet- induced cardiac pathology are often attributed to the systemic effects of obesity, such as hypertension, hyperglycemia, dyslipidemia, and inflammatory mediators;however, signal transduction pathways intrinsic to cardiomyocyte function and hypertrophy are altered in Western diet-fed hearts. The post- translational O-linked attachment of a -N-acetylglucosamine (O-GlcNAc) sugar to serine/threonine residues of proteins is an important mediator of signal transduction, with a single enzyme, O-GlcNAc transferase (OGT), catalyzing the attachment of O-GlcNAc to proteins. Post-translational modification of chromatin-associated proteins and formation of chromatin-modifying complexes cause chromatin to relax or contract thus activating or repressing gene transcription. Interestingly, key components of the chromatin-modifying complex that silences the cardiac fetal gene program and hypertrophy are O- GlcNAcylated and also interact with OGT. Despite this knowledge, the role of the O-GlcNAc pathway in regulating chromatin signaling and downstream cardiomyocyte hypertrophy in the heart has not yet been determined. In preliminary studies, we found increased cardiac O-GlcNAc levels following short-term consumption of a Western diet in young mice, O-GlcNAc-mediated blunting of hypertrophic signaling in isolated mouse cardiomyocytes, and identified several key chromatin proteins that have the potential for O-GlcNAcylation. As the Western diet and chronic increases in O-GlcNAc are both deleterious to cardiomyocytes, and OGT is a component of chromatin-modifying complexes, we propose to test the hypothesis that the Western diet modulates chromatin signaling in the heart via the O-GlcNAc pathway by undertaking two specific aims: Specific Aim #1: Identify O-GlcNAc-modified cardiac chromatin proteins Specific Aim #2: Determine if the O-GlcNAc pathway blunts cardiac hypertrophy by promoting formation of chromatin-modifying complexes The successful completion of the proposed studies will provide a better insight into the etiology of O-GlcNAc- and Western diet-induced alterations in the cellular and molecular mechanisms underlying cardiomyocyte dysfunction. These findings will provide a foundation for the development of new and novel therapeutic targets for the prevention and treatment of cardiac pathology induced by the Western diet. PUBLIC HEALTH RELEVANCE: Diets high in sugar and saturated fat (commonly referred to as "Western" diets) are associated with the development of cardiovascular disease and can exert detrimental effects on the heart muscle independently of any changes in blood pressure, glucose or lipid levels. In preliminary experiments, we found that the Western diet also alters the attachment of sugars (O-GlcNAc) to proteins;this attachment has been linked to metabolic disease, and is elevated in the heart in response to diabetes. In this series of experiments, we propose to examine if increased O-GlcNAc production is responsible for altering mechanisms of gene expression and anticipate that our findings will provide a better understanding of the way in which poor nutrition promotes cardiovascular disease.